Qa-1/HLA-E present very similar class I leader-derived peptides to CD/NKG2 receptors on NK cells. CD94/NKG2 receptors appear to be MHC restricted in that they recognize both the class Ib molecule as well as specific peptides. Thus, the presentation of the leader derived peptide is critical for the ability of target cells to trigger receptors on NK cells. The generation of the murine peptide from D-region molecules, which we refer to as Qdm, as well as the Qdm-like peptide from HLA molecules, as Tap-dependent. We have previously shown that 1)processing of the Qdm peptide from mature Dd molecules is independent of proteasome activity, 2) the epitope cannot be generated by directing Dd to the cytosol, and 3) Tap functions to transport the peptide from the cytosol to the ER rather than serving as an accessory molecule for peptide loading in the ER. There are several issues that we will address concerning the processing of Qdm. This includes determining whether the Dd leader targeted to the ER by the E3/19K leader can be processed in this compartment, whether altering the change in the N-region of the leader changes its intracellular trafficking, the role of proteases in this process, and how flanking residues affect processing. Other leader derived epitopes have been reported to be presented by class I molecules in Tap-deficient T2 cells. This issue will be addressed by examining the presentation of these epitopes in other cell types. Two viruses, MHV and HCMV, have genes which encode Qdm or Qdm-like epitopes. We will determine whether these viral genes, as well as the intact viruses, allow for Qdm expression in infected cells. If this occurs, we will then examine the processing and presentation of these viral encoded Qdm epitopes.